Reevaluation of the importance of polymorphic HLA class II alleles and amino acids in the susceptibility of individuals of different populations to type I diabetes

Abstract

Several publications have shown that certain alleles at the HLA-DRB1, -DQA1, and -DQB1 loci are associated with insulin-dependent diabetes mellitus (IDDM). Many of these studies have claimed that HLA-DQalpha1Arg52 and DQbeta1Asp57 showed the strongest association with IDDM, but these results could not be confirmed in different populations. We have recently found that DRbeta1Lys71+ provided major susceptibility to IDDM and that DQbeta1Asp57- had an additive effect to DRbeta1Lys71+ [Zamani et al., 1994a: Eur J Hum Genet 2:177-184]. This was confirmed with haplotype analysis in multiplex IDDM families [Zamani et al., 1996a: J Med Genet 33:899-905]. Therefore, we have reanalyzed the data from the literature on the association of the human leucocyte antigen (HLA) DRB1, DQB1, and DQA1 with IDDM in different ethnic groups to determine whether different amino acids in the antigen binding cleft of HLA class II molecules play a preponderant role in the development of IDDM. The results showed that the DRbeta1Lys71+ allele provided the highest relative risk for IDDM in the Belgian, Danish, Greek Taiwanese, and Chinese population while this was not the case in Norwegians, Sardinians, and Algerians. Indeed, in the Sardinian and Algerian population the DRB1*0401 allele encoding Lys71+ is very rare. Nevertheless, the few positive cases were always in the patient group. We also measured the clinical relevance of the testing for DRbeta1Lys71, DQbeta1Asp57, and DQalpha1Arg52 by calculating a prevalence-corrected positive predictive value (PcPPV), a prevalence corrected negative predictive value (PcNPV), the sensitivity and specificity of these tests. The results indicated that the sensitivity of the test for DRbeta1Lys71+ was lower than for DQalpha1Ag52+ and DQbeta1Asp57-, while testing for DRbeta1Lys71+ was more specific than testing for DQbeta1Asp57- and DQalpha1Arg52+ and that the DRbeta1Lys71+ allele had a higher PcPPV than DQalpha1Arg52+ and DQbeta1Asp57- in all studied populations. These results also showed that testing for DRbeta1LyS71+/+ can be useful in IDDM risk assessment particularly in populations with a high prevalence (P) of IDDM such as the Danish (P[IDDM] = 0.65%). PcPPV for DRbeta1Lys71+/+ was 0.2313 in the Danish, indicating a 23.13% risk for an individual who is homozygous for the genotype DRbeta1Lys71+/+ to develop IDDM. Some mechanisms which might explain the role of these HLA class II alleles in susceptibility to IDDM are discussed.

Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

“…Position -74 is part of the P4 pocket of the DRB1 molecule, which has been consistently implicated in several models for disease prediction in rheumatoid arthritis. 38,39 The predictive value of the P4 pocket has also been demonstrated by others, 2,40,41 and has a strong pocket structural similarity between DRB1*0403 and DQB1*0301, both protective for T1D. 2 Third, several reports suggest the presence of an additional susceptibility locus in the class II, III, and I regions in several autoimmune diseases, although the necessity of fully compensating for the class II effect in these studies is a complicating factor.…”

HLA haplotypes associated with type 1 diabetes mellitus in north indian children

“…On the other hand, HLA-DRB1*15, *0403, *0404, and *0407 have been reported to confer protection against the development of type 1 diabetes in most ethnic groups [11]. Also, the important role played by particular amino acid residues of HLA class II alleles in determining susceptibility of individuals of different populations to type 1 diabetes has been re-evaluated [16].…”

Preferential transmission of maternal allele with DQA1*0301-DQB1*0302 haplotype to affected offspring in families with type 1 diabetes

“…Observations on twins have shown that the concordant rate for development of type 1 diabetes between monozygotic twins is no more than 50% (Tattersall and Pyke 1972; Committee on Diabetic Twins, Japan Diabetes Society 1988; Kaprio et al 1992;Kumar et al 1993). Furthermore, association studies have shown that excess of specific compound heterozygotes DQB1*0302/*0201 in Caucasian populations and DQB1*0302/*0401 in the Japanese was strongly associated with the disease in each population (Ikegami et al 1992;Jenkins et al 1992;Baisch et al 1990;Zamani and Cassiman 1998). This complex mode of inheritance in the diseaseprone families is not explained simply by the polygenic inheritance.…”